ABSTRACT: RESEARCH PROJECT 3 Schizophrenia (SCZ) is a complex psychiatric disorder that presents unique challenges in the study of disease biology. There are no objective biological phenotypes and the etiology is unknown. These lead to tremendous difficulty in diagnosis and treatments. The study of neurobiology underlying this severe psychiatric disorder has been hindered by the lack of access to the tissue of interest ? neurons or other cells like microglia (the resident immune cells) from patients' brain. In recent years, several lines of studies have found that SCZ has high co-occurrence with autoimmune disorders (AIDs). Lately, evidence has also highlighted that microglial activation contributes to the risk of SCZ. Several hypotheses have been proposed regarding these studies. One hypothesis is that common genetic alterations or biological pathways are involved in the pathogenesis of both SCZ and AIDs. Another is the microglial activation hypothesis that pro-inflammatory cytokines such as IL- 1?, IL-6 and TNF-?, produced by chronically activated microglia in the brain, are the fundamental mediators for SCZ. However, genetic overlap between SCZ and AIDs at a genome-wide level is largely unknown due to both complex disorders have a complex genetic architecture. In addition, no studies have tested directly in microglia derived from living patients, and the mechanism of microglial activation in the process of SCZ remains unclear. In this application, we hypothesize that common genetic risk factors contribute to a high incidence between SCZ and AIDs, and that microglial activation is a key step in the development of SCZ. Two specific aims are proposed in this study. In Aim 1, we will identify the shared genetic risk factors between SCZ and AIDs using meta-analysis and polygenic analysis. Potential shared pathways between these disorders are also examined. In Aim 2, we will investigate whether the microglial activation enhance the risk of SCZ. We will first establish induced microglia-like cells (iMGCs) from blood monocytes. We will then characterize and validate our iMGC model by morphology and functional study. Finally we will apply the iMGC model to investigate the role of microglia in the development of SCZ. To our knowledge, we will be the first to investigate the common genetic risk factors/pathways between SCZ and AIDs. We will also be the first to investigate the functions of microglia that are directly induced from blood monocytes of SCZ patients. These studies will allow us to pinpoint if, and to what extent, the immune system, including the AIDs risk genes and microglial activation, involve in the development of SCZ. Overall, our proposal has a potential to identify the immune-related risk factors in the etiology of SCZ, which may in turn lead to the discovery of reliable biomarkers and new therapeutic strategies for the care of SCZ patients. This grant will also pave a way for my career development. As I accumulate data and publications, I will be able to apply for R15/R01 grants starting at Years 2-3. My optimal goal is to get an R01 by the end of this grant and establish myself to be an independent investigator.